PROJECT SUMMARY The identification of novel cancer susceptibilities and genomic features predictive of those vulnerabilities can lead to new targeted therapeutic strategies. For example, activating mutations in BRAF or EGFR predict sensitivity to small molecule inhibitors of these proteins that demonstrate improved efficacy and favorable side effect profiles compared to standard cytotoxic chemotherapies in melanoma and non-small cell lung cancers, respectively. While immunotherapies have recently demonstrated dramatic clinical activity in some cancers, thus far these agents benefit only a subset of patients. As a result, targeted agents will remain an important therapeutic modality in clinical oncology. Thus, it is critical to incorporate comprehensive genomic profiling of cancers with functional studies to identify novel cancer vulnerabilities attributable to specific genomic features. Towards this end, we have found that cancer cell lines harboring a highly-recurrent genomic alteration (present in melanoma, non-small cell lung cancer, pancreatic cancer, and glioblastoma among others) are dependent on protein components of the methylosome, which catalyzes the transfer of methyl groups to arginine side- chains of multiple target proteins. This project seeks to further investigate the mechanistic basis and translational implications of this association through an integrative and collaborative approach. Specifically, I aim to identify therapeutic strategies to exploit this cancer dependency, to identify biological processes regulated by the methylosome that might serve as additional therapeutic targets, and to identify cellular effectors sufficient to compensate for this dependency on the methylosome. I am currently an Instructor of Medicine affiliated with the Division of Thoracic Oncology at Dana-Farber Cancer Institute. Over 75% of my time is devoted to my research interests under the mentorship of Levi Garraway at Dana-Farber Cancer Institute and the Broad Institute, with the remainder dedicated to clinical practice. My goal is to successfully transition to a tenure-track position as an independent investigator. To achieve this, I am seeking a K08 award to provide support for an additional period of mentored research to gain experience with methyltransferase biology, the use of mouse model systems for preclinical testing of therapeutic strategies, computational and statistical methodologies necessary for the analysis of large biological datasets, and functional genomic approaches necessary to achieve my immediate research goals. Under the guidance of a distinguished mentorship and advisory committee, I will have access to the resources and support necessary to establish a successful independent research program focusing on the identification and characterization of genetic determinants of cancer susceptibility and drug resistance in an effort to develop and refine therapeutic strategies for refractory cancers.